Since its introduction, the measurement of D-dimer in plasma or whole
blood has found a number of uses in clinical practice. These uses are
as follows:

High negative predictive value for excluding venous thromboembolism,
or VTE.

Elevated levels in patients with increased fibrinolysis and a sensitive
(but not specific) diagnostic test for disseminated intravascular coagulation.

Elevated levels following completion of oral anticoagulation are associated
with VTE.

Independent marker of increased risk of future myocardial infarction
in patients evaluated for chest pain. Of particular importance is the
use of the D-dimer in the diagnostic algorithm for deep venous thrombosis
(DVT) and pulmonary embolism (PE), two forms of VTE that are common,
and in the case of PE, potentially fatal. D-dimer levels become elevated
in the blood of patients with VTE due to fibrinolysis of newly formed
blood clots, and this pathophysiologic abnormality has been targeted
for diagnostic purposes. In concept, if the D-dimer level is sufficiently
low in a patient suspected of having VTE, then the diagnosis can be
excluded. In practice the use of the D-dimer test in the diagnostic
algorithm is usually more complex because the patient’s pretest probability
of disease may also be taken into consideration before a D-dimer is
ordered. Nonetheless, because of the serious nature of this clinical
decision it is critical that laboratories accurately measure and report
D-dimer levels.

The CAP Coagulation Resource Committee considered this to be an important
patient safety issue. So to gain a better understanding of the potential
variation in how laboratories are measuring and reporting D-dimer levels,
the committee conducted a questionnaire survey of 4,857 CG1 and CG2 participants
in the 2004-C Surveys mailing. The questions were designed to determine
the D-dimer methods being used, the type of units being reported [fibrinogen
equivalent units (FEU) versus D-dimer units (D-DU)], the magnitude of
units being reported, whether the test was being used to exclude VTE,
and the cutoff values being used to exclude VTE. These data were compared
with the manufacturers’ recommended cutoff values for excluding VTE.

Of the 4,857 surveyed, 2,232 (46 percent) indicated that they report
the D-dimer. Surveys were returned by 2,018 (42 percent of the total,
90 percent of those reporting the D-dimer). Of this group of 2,018 laboratories,
1,506 (75 percent) reported using the D-dimer to exclude VTE. Among these
1,506 laboratories, 11 different methods were being used (eight to 466
users per method): A quantitative method was used by 1,460 (96.8 percent),
a whole blood point-of-care method by 17 (1.1 percent), and a semiquantitative
method by 29 (1.9 percent). Fifty-nine percent reported FEU and 41 percent
reported D-DU. Surprisingly, 126 laboratories (eight percent) did not
know the type of units they were using. Eight different combinations of
type and magnitude of units were reported: ng/mL FEU, ng/mL D-DU, μg/L
FEU, μg/L D-DU, μg/mL FEU, μg/mL D-DU, mg/L FEU, and mg/L
D-DU. All methods showed variability in the type and magnitude of the
units. Another important observation: 488 laboratories (39 percent) were
using a D-dimer cutoff value above that recommended by the manufacturer.

These data indicate several aspects of D-dimer testing that are of significant
concern. The first and greatest concern is that many laboratories appear
to be using cutoff values that are too high for their particular method.
This may lead to many patients being erroneously excluded from VTE. Second,
some laboratories don’t know which type of unit they are reporting (FEU
versus D-DU). This makes it impossible to know with certainty what cutoff
value should be communicated to clinicians. Third, a small number of laboratories
are using semiquantitative methods for excluding VTE. This may be inappropriate
because semiquantitative methods have not been validated in the medical
literature for the exclusion of VTE.

How should laboratories respond to this problem? The Coagulation Resource
Committee is recommending that laboratories that wish to use the D-dimer
test for excluding VTE consider the following guidelines to help remedy
these problems:

Verify that the D-dimer method being used has been validated for VTE
screening. Determine whether the method has been validated as such by
carefully reading the package insert or communicating directly with
the manufacturer. If the method has been validated, the manufacturer
should be able to provide a cutoff value for the exclusion of DVT, PE,
or both DVT and PE. In addition, the manufacturer should state if the
cutoff value can be used in all patients suspected of VTE, or only in
those with certain pretest probabilities of VTE (low, moderate, or high
pretest probability). If laboratories want to modify the manufacturer’s
recommended cutoff, or establish their own cutoff on a method without
a known value, then they should conduct their own validation study before
implementation. It is also important to be aware that with some methods,
the recommended cutoff for exclusion of VTE is well below the upper
limit of the reference range. In these cases it is not sufficient to
set the cutoff at the upper limit of normal; instead, it must be set
below that level.

Communicate to clinicians the D-dimer cutoff value for exclusion of
VTE. This can be accomplished in a number of ways. Examples are a written
indication of the cutoff within the patient report or a written memo
to clinicians.

Verify that the type and magnitude of D-dimer units are being correctly
stated on patient reports. The units that the D-dimer method generates
directly can be determined from the package insert for the method being
used. Some laboratories may be converting the units stated in the package
insert into different units for the patient report. If this is being
done, one should verify that the calculations are correct. For example,
a method may generate data as μg/mL FEU, and the laboratory may
wish to convert this to ng/mL D-DU. In this situation one must convert
both the "unit magnitude" (μg/mL to ng/mL) and the "unit type"
(FEU to D-DU). A critical concept for this calculation is that the mass
of one unit of FEU is twice that of the mass of one unit of D-DU (1
ng/mL D-DU equals 2 ng/mL FEU). So in this example the correct conversion
factor is 500, which is calculated as follows: 1μg/mL FEU X (1000
ng/1μg) X (1D-DU/ 2FEU) = 500 ng/mL D-DU. To avoid calculation
errors, it may be prudent for laboratories to use the units the manufacturer
recommends rather than to make a mathematical conversion.

Dr. Cunningham, chair of the CAP Coagulation Resource Committee, is
director of the hematology laboratory, Department of Pathology, University
of Kansas Medical Center, Kansas City, Kan. Dr. Olson, immediate past
chair of the Coagulation Resource Committee, is professor and vice chair
for clinical affairs, Department of Pathology, University of Texas Health
Science Center at San Antonio, and director of clinical laboratories,
University Health System.